DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction). In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate. In estimates made for mice, on average approximately 1,500 to 7,000 DNA lesions occur per hour in each mouse cell, or about 36,000 to 160,000 per cell per day (Vilenchik & Knudson 2000). In any cell some DNA damage may remain despite the action of repair processes. The accumulation of unrepaired DNA damage is more prevalent in certain types of cells, particularly in non-replicating or slowly replicating cells, such as cells in the brain, skeletal and cardiac muscle. DNA damage and mutation To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of errors that occur in DNA. Damages and mutation are fundamentally different. DNA damages are physical abnormalities in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and thus they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of decrements in function, characteristic of aging, associated with accumulation of DNA damages, are given later in this article. In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation. Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging. The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander (1967). By the early 1980s there was significant experimental support for this idea in the literature (Gensler & Bernstein, 1981). By the early 1990s experimental support for this idea was substantial, and furthermore it had become increasingly evident that oxidative DNA damage, in particular, is a major cause of aging (Bernstein & Bernstein, 1991; Ames & Gold, 1991; Holmes et al., 1992; Rao & Loeb, 1992; Ames et al., 1993). In a series of articles from 1970 to 1977, PV Narasimh Acharya, Phd. (1924–1993) theorized and scientifically proved that cells undergo "irreparable DNA damage," whereby DNA crosslinks occur when both normal cellular repair processes fail and cellular apoptosis does not occur. Specifically, PVN Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate." (PVN Acharya; PVN Acharya & Bjorksten et al.) Acharya's research also showed how irreparable DNA damage is caused by environmental pollutants, low dose ionizing radiation and food additives, particularly nitrites and nitrates and such damage to the DNA is a causal factor for pre-mature aging and cancer. Age-associated accumulation of DNA damage and decline in gene expression In tissues composed of non- or infrequently replicating cells, DNA damage can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damage is usually measured directly. Numerous studies of this type have indicated that oxidative damage to DNA is particularly important. The loss of expression of specific genes can be detected at both the mRNA level and protein level. Brain The adult brain is composed in large part of terminally differentiated non-dividing neurons. Many of the conspicuous features of aging reflect a decline in neuronal function. Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to the present in at least 29 studies, too many to describe here. A review of the role of DNA damage in aging, including a comprehensive summary of the studies showing DNA damage accumulation with age in brain, muscle, liver and kidney, was presented by Bernstein et al. (2008). Here, we mention only some recent studies involving rodents plus one human study. Rutten et al. (2007) showed that single-strand breaks accumulate in the mouse brain with age. Sen et al. (2007) showed that DNA damages which block the polymerase chain reaction in rat brain accumulate with age. Swain and Rao (2011) observed marked increases in several types of DNA damages in aging rat brain, including single-strand breaks, double-strand breaks and modified bases (8-OHdG and uracil). Wolf et al. (2005) also showed that the oxidative DNA damage 8-OHdG accumulates in rat brain with age. Similarly, it was shown that as humans age from 48–97 years, 8-OHdG accumulates in the brain (Mecocci et al., 1993). Decrements in function were noted in aging human brain, where transcription of a set of evaluated genes declines with age from 40 to 106 years (Lu et al., 2004). These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. In the brain, promoters of genes with reduced expression have markedly increased DNA damage (Lu et al., 2004). In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al. (2004) concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a program of brain aging that starts early in adult life. Muscle Muscle strength, and stamina for sustained physical effort, have decrements in function with age in humans and other species. Skeletal muscle is a tissue composed largely of multinucleated myofibers, elements that arise from the fusion of mononucleated myoblasts. Accumulation of DNA damage with age in mammalian muscle has been reported in at least 18 studies (Bernstein et al., in press 2008) since 1971. We will mention here only two of the more recent studies in rodents plus one in humans. Hamilton et al. (2001) reported that the oxidative DNA damage 8-OHdG accumulates in heart and skeletal muscle (as well as in brain, kidney and liver) of both mouse and rat with age. In humans, increases in 8-OHdG with age were reported for skeletal muscle (Mecocci et al., 1999). Catalase is an enzyme that removes hydrogen peroxide, a reactive oxygen species, and thus limits oxidative DNA damage. In mice, when catalase expression is increased specifically in mitochondria, oxidative DNA damage (8-OHdG) in skeletal muscle is decreased and lifespan is increased by about 20% (Schriner et al., 2005; Linford et al., 2006). These findings suggest that mitochondria are a significant source of the oxidative damages contributing to aging. Protein synthesis and protein degradation decline with age in skeletal and heart muscle, as would be expected, since DNA damage blocks gene transcription. In a recent study (Piec et al., 2005) found numerous changes in protein expression in rat skeletal muscle with age, including lower levels of several proteins related to myosin and actin. Force is generated in striated muscle by the interactions between myosin thick filaments and actin thin filaments. Liver Liver hepatocytes do not ordinarily divide and appear to be terminally differentiated, but they retain the ability to proliferate when injured. With age, the mass of the liver decreases, blood flow is reduced, metabolism is impaired, and alterations in microcirculation occur. At least 21 studies (Bernstein et al., in press 2008) have reported an increase in DNA damage with age in liver. For instance, Helbock et al. (1998) estimated that the steady state level of oxidative DNA base alterations increased from 24,000 per cell in the liver of young rats to 66,000 per cell in the liver of old rats. Kidney In kidney, changes with age include reduction in both renal blood flow and glomerular filtration rate, and impairment in the ability to concentrate urine and to conserve sodium and water. DNA damages, particularly oxidative DNA damages, increase with age (at least 8 studies)(Bernstein et al., in press 2008). For instance Hashimoto et al. (2007) showed that 8-OHdG accumulates in rat kidney DNA with age. Long-lived stem cells Tissue-specific stem cells produce differentiated cells through a series of increasingly more committed progenitor intermediates. In hematopoiesis (blood cell formation), the process begins with long-term hematopoietic stem cells that self-renew and also produce progeny cells that upon further replication go through a series of stages leading to differentiated cells without self-renewal capacity. In mice, deficiencies in DNA repair appear to limit the capacity of hematopoietic stem cells to proliferate and self-renew with age (Rossi et al., 2007). Sharpless and Depinho (2007) reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging. They speculated that stem cells grow old, in part, as a result of DNA damage. DNA damage may trigger signalling pathways, such as apoptosis, that contribute to depletion of stem cell stocks. This has been observed in several cases of accelerated aging and may occur in normal aging too (Freitas and de Magalhaes, 2011). Mutation theories of aging A popular idea, that has failed to gain significant experimental support, is the idea that mutation, as distinct from DNA damage, is the primary cause of aging. As discussed above, mutations tend to arise in frequently replicating cells as a result of errors of DNA synthesis when template DNA is damaged, and can give rise to cancer. However, in the mouse there is no increase in mutation in the brain with aging (Dolle et al., 1997; Stuart et al., 2000; Hille et al., 2005). Mice defective in a gene (Pms2) that ordinarily corrects base mispairs in DNA have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly (Narayanan et al., 1997). On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation (Dolle et al., 2006). One variation of the idea that mutation is the basis of aging, that has received much attention, is that mutations specifically in mitochondrial DNA are the cause of aging. Several studies have shown that mutations accumulate in mitochondrial DNA in infrequently replicating cells with age. DNA polymerase gamma is the enzyme that replicates mitochondrial DNA. A mouse mutant with a defect in this DNA polymerase is only able to replicate its mitochondrial DNA inaccurately, so that the mutation rate is 500-fold higher than in normal mice. Yet these mice showed no obvious features of rapidly accelerated aging (Vermulst et al., 2007). The probable explanation for the apparent lack of effect of the additional mutations in mitochondrial DNA is that, within a typical cell, there are large numbers of mitochondria and each mitochondrion can have multiple copies of mitochondrial DNA. Since most mutations are recessive, any particular deleterious mutation would not be expected to have a pronounced effect when many copies of the correct DNA sequence are present in the same and in other mitochondria in the cell. Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging. Dietary Restriction In rodents, caloric restriction slows aging and extends lifespan. At least 4 studies have shown that caloric restriction reduces 8-OHdG damages in various organs of rodents. One of these studies (Hamilton et al., 2001) showed that caloric restriction reduced accumulation of 8-OHdG with age in rat brain, heart and skeletal muscle, and in mouse brain, heart, kidney and liver. More recently, Wolf et al. (2005) showed that dietary restriction reduced accumulation of 8-OHdG with age in rat brain, heart, skeletal muscle, and liver. Thus reduction of oxidative DNA damage is associated with a slower rate of aging and increased lifespan. Inherited defects that cause premature aging If DNA damage is the underlying cause of aging, it would be expected that humans with inherited defects in the ability to repair DNA damages should age at a faster pace than persons without such a defect. Numerous examples of rare inherited conditions with DNA repair defects are known. Several of these show multiple striking features of premature aging, and others have fewer such features. Perhaps the most striking premature aging conditions are Werner syndrome (mean lifespan 47 years), Huchinson-Gilford Progeria (mean lifespan 13 years), and Cockayne syndrome (mean lifespan 13 years). Werner syndrome is due to an inherited defect in an enzyme (a helicase and exonuclease) that acts in base excision repair of DNA (e.g. Harrigan et al., 2006). Hutchinson-Guilford Progeria is due to a defect in Lamin A protein which forms a scaffolding within the cell nucleus to organize chromatin and is needed for repair of double-strand breaks in DNA (Liu et al., 2007). Cockayne Syndrome is due to a defect in a protein necessary for the repair process, transcription coupled nucleotide excision repair, which can remove damages, particularly oxidative DNA damages, that block transcription (D’Errico et al., 2007). In addition to these three conditions, several other human syndromes, that also have defective DNA repair, show several features of premature aging. These include ataxia telangiectasia, Nijmegen breakage syndrome, some subgroups of xeroderma pigmentosum, trichothiodystrophy, Fanconi anemia, Bloom syndrome and Rothmund-Thomson syndrome. In addition to human inherited syndromes, experimental mouse models with genetic defects in DNA repair show features of premature aging and reduced lifespan (e.g. Vogel et al., 1999; Niedernhoffer et al., 2006; Mostoslavsky et al., 2006). Lifespan in different mammalian species Studies comparing DNA repair capacity in different mammalian species have shown that repair capacity correlates with lifespan. The initial study of this type, by Hart and Setlow (1974), showed that the ability of skin fibroblasts of seven mammalian species to perform DNA repair after exposure to a DNA damaging agent correlated with lifespan of the species. The species studied were shrew, mouse, rat, hamster, cow, elephant and human. This initial study stimulated many additional studies involving a wide variety of mammalian species, and the correlation between repair capacity and lifespan generally held up. In one of the more recent studies, Burkle et al. (2005) studied the level of a particular enzyme, poly(ADP-ribose) polymerase, which is involved in repair of single-strand breaks in DNA. They found that the lifespan of 13 mammalian species correlated with the activity of this enzyme. In addition, they found that humans who lived past 100 years had a significantly higher activity of this enzyme than younger individuals. Conclusions Numerous studies have shown that DNA damage accumulates in brain, muscle, liver, kidney, and in long-lived stem cell. These accumulated DNA damages are the likely cause of the decline in gene expression and loss of functional capacity observed with increasing age. On the other hand, accumulation of mutations, as distinct from DNA damages, is not a plausible candidate as the primary cause of aging. A calorie-restricted diet in mammals improves lifespan, and this improvement is associated with a decrease in oxidative DNA damage. Several inherited genetic defects in ability to repair DNA damage give rise to premature aging suggesting a causal relationship between DNA damage and aging. In comparisons of different mammalian species that differ in lifespan, DNA repair capacity is found to correlate with lifespan. The principal source of the DNA damages leading to normal aging appears to be reactive oxygen species, produced as byproducts of normal cellular metabolism. See also * Aging brain * Biological immortality * DNA damage (naturally occurring) * DNA repair * Life expectancy * Longevity * Maximum life span * Rejuvenation (aging) * Senescence * Telomere References * Acharya, PV. The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides. Johns Hopkins Med J Suppl, June 1971, 1: 254-260. PMID 5055816. * Acharya, PVN. 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